Facilitated transport of 6-mercaptopurine and 6-thioguanine and non-mediated permeation of 8-azaguanine in novikoff rat hepatoma cells and relationship to intracellular phosphoribosylation

Plagemann, Peter G.W.; März, Richard; Wohlhueter, Robert M.; Graff, Jon C.; Zylka, J M

doi:10.1016/0005-2736(81)90294-7

Cited by 18 publications

(6 citation statements)

References 25 publications

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“…Hypoxanthine protects against the cytodestructive properties of thioguanine by preventing the anabolism of the purinethiol to its nucleotide level; this may occur through competition between hypoxanthine and 6-thioguanine at several levels. These include (a) the transport carrier for hypoxanthine/guanine (Plagemann et al, 1981); (b) the enzyme HGPRT; and (c) 5-phosphoribosyl 1-pyrophosphate (PRPP), with the activation of hypoxanthine to inosine 5'-phosphate leading to a decreased availability of PRPP for the synthesis of 6-thioguanosine 5'-phosphate by HGPRT. Information of this kind would appear to be critical before an agent such as 6-thioguanine is tested for its capacity to induce maturation in a clinical setting.…”

Section: Squamous Cell Carcinoma As a Model Of Blocked Maturationmentioning

confidence: 99%

The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach

Sartorelli¹

1985

Br J Cancer

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it was possible to demonstrate that physiological levels of retinoic acid and epidermal growth factor were capable of preventing the differentiation of these malignant keratinocytes into a mature tissue-like structure. The terminal differentiation caused by certain antineoplastic agents was investigated in HL-60 promyelocytic leukaemia cells to provide information on the mechanism by which chemotherapeutic agents induce cells to by-pass a maturation block. The anthracyclines aclacinomycin A and marcellomycin were potent inhibitors of N-glycosidically linked glycoprotein biosynthesis and transferrin receptor activity, and active inducers of maturation; temporal studies suggested that the biochemical effects were associated with the differentiation process. 6-Thioguanine produced cytotoxicity in parental cells by forming analog nucleotide. In hypoxanthine-guanine phosphoribosyltransferase negative HL-60 cells the 6-thiopurine initiated maturation; this action was due to the free base (and possibly the deoxyribonucleoside), a finding which separated termination of proliferation due to cytotoxicity from that caused by maturation.

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Section: Squamous Cell Carcinoma As a Model Of Blocked Maturationmentioning

confidence: 99%

The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach

Sartorelli¹

1985

Br J Cancer

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“…The amount of 6-TG taken up by LoVo 6-TG r cells is significantly lower compared with the parental cells. In this regard, 6-TG appears to be transported across the cell membrane of rat hepatoma cells through a facilitated mechanism (Plagemann et al, 1981), probably by the hypoxanthine carrier. Our results demonstrate that 6-TG is transported in LoVo cells by a facilitated mechanism, which is altered in 6-TG r cells.…”

Section: Resultsmentioning

confidence: 99%

6-thioguanine resistance in a human colon carcinoma cell line with unaltered levels of hypoxanthine guanine phosphoribosyltransferase activity

Bemi¹,

Turchi²,

Margotti³

et al. 1999

Int. J. Cancer

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“…Since many electrophilic toxicants are converted to their active forms by cellular metabolism, the ability of a potential scavenger to enter cells is a major determinant of efficacy. DTP is known to be a good substrate for the endogenous purine transporter (40), facilitating its transport into cells, but whether DUA is also a substrate for this transport system is unknown.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of the Reaction of a Potential Chemopreventive Agent, 2,6-Dithiopurine, and Its Major Metabolite, 2,6-Dithiouric Acid, with Multiple Classes of Electrophilic Toxicants

1996

Chem. Res. Toxicol.

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Purinethiols are a class of potential cancer chemopreventive agents that exhibit nucleophilic scavenging activity against the carcinogenic electrophile benzo[a]pyrene diol epoxide (BPDE). Of the purinethiols tested previously, 2,6-dithiopurine (DTP), exhibited the highest scavenging activity for BPDE when tested either in vitro or in vivo. Sulfur-based nucleophiles are typically classified as "soft" nucleophiles, showing selectivity in nucleophilic substitution reactions for "soft", easily polarizable electrophiles. It was of interest to determine whether electrophilic toxicants other than BPDE react facilely with DTP, and whether 2,6-dithiouric acid (DUA), the major in vivo metabolite of DTP, also has scavenging activity. Four diverse toxicants tested in the present work, acrolein, melphalan, dimethyl sulfate, and cisplatin, all react facilely with DTP in vitro near neutral pH. These toxicants are expected to react as "soft" electrophiles. Furthermore, each of these compounds, as well as BPDE, reacts with DUA with rate constants comparable to the analogous rate constants for reaction with DTP. In contrast, several toxicants classified as "hard" electrophiles (ethyl methanesulfonate, methylnitrosourea, ethylnitrosourea, 1-methyl-3-nitro-1-nitrosoguanidine) show no appreciable reaction with DTP. These results suggest that both DTP and its major metabolite act as "soft" nucleophiles in nucleophilic substitution reactions and may be effective in scavenging a wide range of toxicants that react as "soft" electrophiles.

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Facilitated transport of 6-mercaptopurine and 6-thioguanine and non-mediated permeation of 8-azaguanine in novikoff rat hepatoma cells and relationship to intracellular phosphoribosylation

Cited by 18 publications

References 25 publications

The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach

The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach

6-thioguanine resistance in a human colon carcinoma cell line with unaltered levels of hypoxanthine guanine phosphoribosyltransferase activity

Kinetics of the Reaction of a Potential Chemopreventive Agent, 2,6-Dithiopurine, and Its Major Metabolite, 2,6-Dithiouric Acid, with Multiple Classes of Electrophilic Toxicants

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